The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
Staphylococcus aureus, a commensal microorganism that typically colonizes the anterior nares of 30% of the human population, is the leading cause of bacterial infections in the US. Staphylococcus aureus is a versatile pathogen that can express an array of virulence factors, including adhesins [e.g. fibronectin binding proteins (FnBPs) and protein A] that mediate binding to host cells, enzymes (e.g. proteases and lipases), toxins [e.g. alpha-haemolysin and Panton-Valentine leukocidin (PVL)], phenol-soluble modulins and capsular polysaccharides. Expression of these virulence factors is controlled by complex staphylococcal regulatory networks, including the accessory gene regulator (agr) system, and these genes vary between strains. Methicillin resistance in S. aureus results from acquisition of the mecA gene located within the mobile element known as the staphylococcal cassette chromosome mec (SCCmec). Until recently, eight SCCmec types were defined according to the SCCmec type and the chromosomal background determined by multilocus sequence typing.
Staphylococcus aureus strains have developed resistance to numerous antibiotics while MRSA, which have developed resistance to most if not all available antibiotic therapy, are very prevalent in hospitals in the US. These antibiotic resistant strains of MRSA also contain a number of proteins that are associated with the clinical virulence of these MRSA strains.
Methicillin resistant Staphylococcus aureus (MRSA) emerged in hospitals in the 1960s and is now the leading cause of hospital-associated infections. This hospital- or healthcare-associated MRSA (HA-MRSA) infection occur in individuals with risk factors for infection (e.g., surgery patients or immunocompromised patients). In contrast, community-associated MRSA (CA-MRSA) infections, first reported in the 1990s, occur in individuals without antecedent healthcare exposure or without such risk factors. Since the sixth decade of the 20th century, hospital and community acquired Staphylococcus aureus resistant infections have been noted in the following groups which are now considered high risk for infections of this organism which display resistance to multiple antibiotics: patients who are post-surgery or are in intensive care units or are in emergency rooms of hospitals, household contacts of individuals with antibiotic resistant Staphylococcus aureus, and individuals who are compromised in their ability to mount an immune response (innate or adaptive) against invasive infectious organisms: the very young (1), the very old, individuals with HIV or cystic fibrosis, institutionalized persons (nursing homes, military barracks, prisons), or individuals in underserved communities. Millions of cases of clinically significant infections of invasive strains of Staphylococcus aureus occur per year in the United States with over 100,000 deaths per year (2). In the beginning, the organisms responsible for these infections were only resistant to methicillin, but more recently, resistance to other antibiotics have been noted (clindamycin, vancomycin, daptomycin, mupirocin).
S. aureus has numerous cell surface proteins and secreted toxins that contribute to virulence by promoting evasion of the host innate immune system. In the past few years, the MSA300 strain has risen from 5% to a position of 42% of isolates in the United States, overtaking USA400 (3) and displacing other strains (ST30, ST80, ST93, and ST50). Many of these strains carry one or more of the following virulence factors:                1. Enterotoxins such as sek2 and seq2 (4);        2. The exotoxin proteins such as hemolysin A, which form pores in the membranes of cells by oligomerization, thereby disrupting the integrity of pulmonary vascular endothelial cells and alveolar cells (5-10). These exotoxins cause necrotizing pneumonia and lysis of leukocytes;        3. Protein A, which is a protein on the surface of Staphylococcus aureus, which inhibits opsonization or uptake of Staphylococcus aureus by phagocytes and promotes inflammation (7, 11-13);        4. Coagulases, which promote the walling-off of pockets of infectious organisms to generate abscesses (14-15);        5. Staphylococcal proteins which provide metabolic functions contributing to the phenotype of virulence in mouse models (such as the heme uptake protein IsdB) (16).        
Given the rise of virulent organisms which display antibiotic resistance, the goal of development of MRSA vaccines for high risk populations has emerged as an important priority, which unfortunately has not yet been realized.
One factor that could prevent the success of vaccination is that the patients who are admitted to hospitals are often of advanced chronological age, are debilitated and/or immunosuppressed by the presence of chronic disease (17-20). These patients often do not respond to vaccination due to the diminished expression of CD40L in the CD40L helper T cells of these people (21-22). Another problem is that passive immunotherapy with opsonizing antibodies does not completely protect individuals against MRSA.